Immediate release medicinal compositions for oral use

ABSTRACT

The present invention relates to an immediate release oral pharmaceutical composition which comprises as an active ingredient calcium salt of a benzylsuccinic acid derivative represented by the formula:  
                 
 
     or its hydrate, which is useful as an agent for the treatment of diabetes.

TECHNICAL FIELD

[0001] The present invention relates to an immediate release oralpharmaceutical composition useful as an agent for the treatment ofdiabetes.

BACKGROUND OF THE INVENTION

[0002] Calcium salt of a benzylsuccinic acid derivative (chemical name:(2S)-2-benzyl-3-(cis-hexahydro-2-iso-indolinylcarbonyl)propionic acid)represented by the formula:

[0003] or its hydrate, which is an active ingredient in thepharmaceutical composition of the present invention, has a remarkablelowering action of blood sugar and has been known as a compound usefulas an agent for the treatment of diabetes (Japanese Patent Laid-Open No.356459/1992).

[0004] Sulfonylurea agents (SU agents) such as glibenclamide, gliclazideand the like which have been frequently used for the treatment ofdiabetes take long to exert their effects and have persisting effectsfor several hours, so that it has been pointed out a problem that a riskof hypoglycemic symptoms increases conversely. For example, when SUagent is taken at a dose of sufficiently suppressing postprandialhyperglycemia, a problem that hypoglycemia is caused between meals cannot be avoided. However, since effects of the present compound areshortly persistent, it is expected as a therapeutic agent forhyperglycemia which corrects only postprandial hyperglycemic conditionwithout causing hypoglycemic condition between meals.

[0005] Rapid absorption after taking a drug in addition to earlyexcretion of an active component from blood is required to correct onlypostprandial hyperglycemic condition without causing hypoglycemiccondition between meals. Thus, development of immediate releasepreparations is needed in postprandial hyperglycemia treatment, whereindisintegration of the pharmaceutical composition and dissolution of theactive ingredient are excellent. Generally, it is necessary forimmediate release preparations to usually have an ability of about 75%or more drug release (drug dissolution) within 20 minutes after takingthe drug (Iyakuhin no Kaihatsu [Development of medicines] Vol.11,pp.65-77, published by Hirokawa Shoten). It is concerned that thepresent compound is problematic in dissolution since it is poorlysoluble in water. Therefore, in order to solve the problem, earlydevelopment of excellent immediate release preparations has been greatlydesired.

DISCLOSURE OF THE INVENTION

[0006] The present invention relates to an immediate release oralpharmaceutical composition which comprises as an active ingredientcalcium salt of a benzylsuccinic acid derivative represented by theformula:

[0007] or its hydrate.

[0008] The invention relates to an immediate release oral pharmaceuticalcomposition which comprises as an active ingredient calcium salt of thebenzylsuccinic acid derivative represented by the above formula (I) orits hydrate, characterized by comprising at least silicon dioxide.

[0009] The invention relates to an immediate release oral pharmaceuticalcomposition which comprises as an active ingredient calcium salt of thebenzylsuccinic acid derivative represented by the above formula (I) orits hydrate, characterized by comprising at least partly pregelatinizedStarch.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a graph showing a dissolution of various tabletsdescribed in Examples 1 and 2 and in Reference Example 1 in whichdihydrate of calcium salt of the benzylsuccinic acid derivative of theabove formula (I) is an active ingredient. The vertical and thehorizontal axes denote percents of dissolution (%) of the activeingredient and time periods (minute) passed after the start of thetests, respectively.

[0011]FIG. 2 is a graph showing a dissolution of various tabletsdescribed in Examples 3 to 6 and in Reference Examples 2 to 9 in whichdihydrate of calcium salt of the benzylsuccinic acid derivative of theabove formula (I) is an active ingredient. The vertical and thehorizontal axes denote percents of dissolution (%) of the activeingredient and time periods (minute) passed after the start of thetests, respectively.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] The present inventors have intensively studied to find immediaterelease oral pharmaceutical compositions comprising as an activeingredient calcium salt of the benzylsuccinic acid derivativerepresented by the above formula (I) or its hydrate, which haveexcellent disintegration and dissolution and are therefore useful asagents for the treatment of diabetes. As a result, it was advantageouslyfound that pharmaceutical compositions prepared by adding at leastsilicon dioxide or partly pregelatinized starch thereto enhance thedisintegration and improve remarkably the dissolution, and thereby thepresent invention has been completed.

[0013] In immediate release oral pharmaceutical compositions comprisingan active ingredient calcium salt of the benzylsuccinic acid derivativerepresented by the above formula (I) or its hydrate, even when tabletsare prepared according to a dry method (direct compressing method), bywhich good disintegration is generally obtained, using disintegrantsusually used such as sodium carboxymethyl starch and low substitutedhydroxypropylcellulose, no preparations having good dissolution wereobtained. The preparations obtained delayed the dissolution and haveabnormally low percentages of dissolution. However, when the tabletswere prepared by adding silicon dioxide, which is usually used as alubricant, extremely excellent dissolution was surprisingly observed.For example, rapid dissolution was observed just after the start of thedissolution test using first fluid of the Japanese Pharmacopoeia, and amaximum dissolution rate was also extremely high.

[0014] Moreover, even when the tablets were prepared according to a wetmethod (wet granule-compressing method), which is generally inferior indisintegration, the silicon dioxide-added preparation exhibitedsurprisingly higher dissolution efficiency compared to the preparationsin which sodium carboxymethyl starch or low substitutedhydroxy-propylcellulose, which is usually used as a disintegrant, wasadded. For example, rapid dissolution was observed just after the startof the dissolution test using first fluid of the Japanese Pharmacopoeia,and a maximum dissolution rate was also extremely high. Furthermore,when tablets were prepared according to the wet methods, the tablets inwhich sodium carboxymethyl starch or low substitutedhydroxypropyl-cellulose, which is usually used as a disintegrant, wasadded were not satisfied because the dissolution rates were still loweven after considerable time periods passed, and particular differenceswere observed in dissolution. On the contrary, when tablets wereprepared according to the wet method employing the addition of partlypregelatinized starch as a disintegrant, good dissolution was observedas in the case with the addition of silicon dioxide. The preparation inwhich carmellose was added as a disintegrant exhibited high dissolutionefficiency as well as the pharmaceutical composition of the presentinvention, but it turned the color of the preparation into pale yellowdue to incompatible combination with the calcium salt of thebenzylsuccinic acid derivative represented by the above formula (I) asthe active ingredient. In addition, it was undesirable because itsstability is not good due to decomposition of the active ingredient.

[0015] That is, the present invention relates to an immediate releaseoral pharmaceutical composition which comprises as an active ingredientcalcium salt of the benzylsuccinic acid derivative represented by theabove formula (I) or its hydrate, characterized by comprising at leastsilicon dioxide or partly pregelatinized starch, wherein it hasremarkable disintegration and dissolution of the active ingredientwithout incompatible combination with calcium salt of the benzylsuccinicacid derivative represented by the above formula (I) and is excellent ina long term storage.

[0016] The calcium salt of the benzylsuccinic acid derivativerepresented by the above formula (I) or its hydrate comprising as anactive ingredient in the present invention can be prepared by themethods described in the references, similar methods thereto or the like(for example, Japanese Patent Laid-Open No. 356459/1992).

[0017] Examples of silicon dioxide used for the present invention caninclude, but are not limited to, light anhydrous silicic acid, hydratedsilicon dioxide and the like. The amount of silicon dioxide to be addedis not limited but the blending from 0.5 to 5% by weight based on thewhole preparation is sufficient.

[0018] As partly pregelatinized starch used for the present invention,various degrees of pregelatinized starch can be used. For example, suchpartly pregelatinized starches include a commercially available partlypregelatinized starch [PCS (trademark)]. The amount of partlygelatinized starch to be added is not limited but the blending from 5 to20% by weight based on the whole preparation is sufficient.

[0019] The oral pharmaceutical compositions of the present invention canapply for various formulations, and typical formulations can includegranules, fine granules, powders, tablets and capsules.

[0020] For example, granules, fine granules and powders can be preparedby conventional methods. Tablets can be prepared using granules or finegranules by conventional methods, or by directly granulating accordingto a dry method (direct compressing method) by conventional methods.Capsules can be prepared by directly filling granules, fine granules ormixed powders in the capsules by conventional methods.

[0021] When the pharmaceutical compositions of the present invention areprepared, suitable additives for each preparation such as diluents,binders, surfactants, lubricants, glidants, coating materials,plasticizers, coloring agents, flavoring agents and the like can befurther used as occasion demands. These additives are those which areusually used pharmaceutically, and any of them can be used so long asthey do not affect adversely on dissolution of and combination with thecalcium salt of the benzylsuccinic acid derivative represented by theabove formula (I) or its hydrate.

[0022] Diluents can include, for example, cellulose or cellulosederivatives such as microcrystalline cellulose and the like; starch orstarch derivatives such as corn starch, wheat starch, cyclodextrin andthe like; sugar or sugar alcohol such as lactose, D-mannitol and thelike; and inorganic diluents such as dried aluminum hydroxide gel,precipitated calcium carbonate, magnesium aluminometasilicate, dibasiccalcium phosphate and the like.

[0023] Binders can include, for example, hydroxypropyl-cellulose,methylcellulose, hydroxypropylmethylcellulose, povidone, dextrin,pullulane, hydroxypropyl starch, polyvinyl alcohol, scacia, agar,gelatin, tragacanth, macrogol and the like.

[0024] Surfactants can include, for example, sucrose esters of fattyacids, polyoxyl stearate, polyoxyethylene hydrogenated castor oil,polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitantrioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitanmonolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate,lauromacrogol and the like.

[0025] Lubricants can include, for example, stearic acid, calciumstearate, magnesium stearate, talc and the like.

[0026] Glidants can include, for example, dried aluminium hydroxide gel,magnesium silicate and the like.

[0027] Coating materials can include, for example,hydroxy-propylmethylcellulose 2910, aminoalkyl methacrylate copolymer E,polyvinylacetal diethylaminoacetate, macrogol 6000, titanium oxide andthe like.

[0028] Plasticizers can include, for example, triethyl citrate,triacetin, macrogol 6000 and the like.

[0029] The pharmaceutical compositions of the present invention areextremely stable, since neither change in its appearance and dissolutionrate nor decomposition of its active ingredient is observed even afterplacing for 1 week under a severe condition of high temperature andhumidity.

[0030] The contents of the present invention are further described indetail by the following Reference Examples, Examples and Test Examples,but the present invention is not limited thereto.

REFERENCE EXAMPLE 1

[0031] Active component  5.0 mg Microcrystalline cellulose 27.5 mgLactose 28.7 mg Corn starch 10.0 mg Low substituedhydroxypropylcellulose  3.0 mg Calcium stearate  0.8 mg [Total] 75.0 mg

[0032] After 412.5 g of microcrystalline cellulose, 430.5 g of lactose,150.0 g of corn starch, 45.0 g of low substitued hydroxypropylcellulose(brand name: L-HPC/LH-11, produced by Shin-Etsu Chemical Co.,Ltd.) and12.0 g of calcium stearate were mixed with 75.0 g of dihydrate ofcalcium salt of the benzylsuccinic acid derivative represented by theformula (I) (active component), the mixture was compressed with apressure of 700 kg using 6 mm diameter round-faced (5R) punch to preparetablets of the above composition.

REFERENCE EXAMPLE 2

[0033] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Carmellose  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8 mg

[0034] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.8 g of carmellose (brand name; NS-300(trademark), produced by Gotoku Yakuhin Co., Ltd.) were mixed with 2.2 gof dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), 4 g. of an aqueoussolution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxypropylcellulose) was added thereto. The mixture was granulated ina mortar, and the granules were passed through screen after drying in ashell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 3

[0035] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Sodium carboxymethyl starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8 mg

[0036] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.8 g of sodium carboxymethyl cellulose(brand name: Primogel [trademark], produced by Matsutani Chemical Co.,Ltd.) were mixed with 2.2 g of dihydrate of calcium salt of thebenzylsuccinic acid derivative represented by the formula (I) (activecomponent), 4 g of an aqueous solution of 6% by weight ofhydroxypropylcellulose (0.24 g as hydroxypropylcellulose) was addedthereto. The mixture was granulated in a mortar, and the granules werepassed through screen after drying in a shell dryer to yield granules of30 mesh (500 μm) or less. Calcium stearate was mixed to the granules tobe at 0.95%, and the mixture was compressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

REFERENCE EXAMPLE 4

[0037] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Low substituedhydroxypropylcellulose  8.0 mg Hydroxypropylcellulose  2.4 mg Calciumstearate  1.2 mg [Total] 126.8 mg

[0038] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.8 g of low substituedhydroxypropylcellulose (brand name; L-HPC/LH-11, produced by Shin-EtsuChemical Co., Ltd.) were mixed with 2.2 g of dihydrate of calcium saltof the benzylsuccinic acid derivative represented by the formula (I)(active component), 4 g of an aqueous solution of 6% by weight ofhydroxypropylcellulose (0.24 g as hydroxypropylcellulose) was addedthereto. The mixture was granulated in a mortar, and the granules werepassed through screen after drying in a shell dryer to yield granules of30 mesh (500 μm) or less. Calcium stearate was mixed to the granules tobe at 0.95%, and the mixtre was compressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

REFERENCE EXAMPLE 5

[0039] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Low substituedhydroxypropylcellulose  8.0 mg Hydroxypropylcellulose  2.4 mg Calciumstearate  1.2 mg [Total] 126.8 mg

[0040] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.8 g of Low substituedhydroxypropylcellulose (brand name; L-HPC/LH-22, produced by Shin-EtsuChemical Co., Ltd.) were mixed with 2.2 g of dihydrate of calcium saltof the benzylsuccinic acid derivative represented by the formula (I)(active component), 4 g of an aqueous solution of 6% by weight ofhydroxypropylcellulose (0.24 g as hydroxypropylcellulose) was addedthereto. The mixture was granulated in a mortar, and the granules werepassed through screen after drying in a shell dryer to yield granules of30 mesh (500 μm) or less. Calcium stearate was mixed to the granules tobe at 0.95%, and the mixture was copressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

REFERENCE EXAMPLE 6

[0041] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Partly pregelatinized starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8 mg

[0042] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose, 0.8 g of partly pregelatinized starch (brandname: PCS [trademark], produced by Asahi Kasei Co., Ltd.), 0.24 g ofhydroxypropylcellulose and 0.12 g of calcium stearate were mixed with2.2 g of dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 7

[0043] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Sodium carboxymethyl starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8 mg

[0044] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose, 0.8 g of sodium carboxymethyl cellulose(brand name: Primogel [trademark], produced by Matsutani Chemical Co.,Ltd.), 0.24 g of hydroxypropyl-cellulose and 1.2 g of calcium stearatewere mixed with 2.2 g of dihydrate of calcium salt of the benzylsuccinicacid derivative represented by the formula (I) (active component), themixture was compressed with a pressure of 500 kg using 7 mm diameterround-faced (9.5R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 8

[0045] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Low substituedhydroxypropylcellulose  8.0 mg Hydroxypropylcellulose  2.4 mg Calciumstearate  1.2 mg [Total] 126.8 mg

[0046] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose, 0.8 g of low substituedhydroxypropylcellulose (brand name; L--HPC/LH-11, produced by Shin-EtsuChemical Co., Ltd.), 0.24 g of hydroxypropyl-cellulose and 0.12 g ofcalcium stearate were mixed with 2.2 g of dehydrate of calcium salt ofthe benzylsuccinic acid derivative represented by the formula (I)(active component), the mixture was compressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

REFERENCE EXAMPLE 9

[0047] Active component  22.0 mg Lactose  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Low substituedhydroxypropylcellulose  8.0 mg Hydroxypropylcellulose  2.4 mg Calciumstearate  1.2 mg [Total] 126.8 mg

[0048] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose, 0.8 g of low substituedhydroxypropylcellulose (brand name; L-HPC/LH-22, produced by Shin-EtsuChemical Co., Ltd.), 0.24 g of hydroxypropyl-cellulose and 0.12 g ofcalcium stearate were mixed with 2.2 g of dihydrate of calcium salt ofthe benzylsuccinic acid derivative represented by the formula (I)(active component), the mixture was compressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

EXAMPLE 1

[0049] Active component  5.0 mg Microcrystalline cellulose 27.5 mgLactose 27.9 mg Corn starch 10.0 mg Low substituedhydroxypropylcellulose  3.0 mg Calcium stearate  0.8 mg Light anhydroussilicic acid  0.8 mg [Total] 75.0 mg

[0050] After 275.0 g of microcrystalline cellulose, 279.0 g of lactose,100.0 g of corn starch, 30.0 g of low substitued hydroxypropylcellulose(brand name: L-HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.), 8.0g of calcium stearate and 8.0 g of light anhydrous silicic acid (brandname: Adsolider [trademark] 101, produced by Freund Industrial Co.,Ltd.) were mixed with 50.0 g of dihydrate of calcium salt of thebenzylsuccinic acid derivative represented by the formula (I) (activecomponent), the mixture was compressed with a pressure of about 700 kgby a tabletting machine using 6 mm diameter round-faced (5R) punch toprepare tablets of the above composition.

EXAMPLE 2

[0051] Active component  5.0 mg Microcrystalline cellulose 27.5 mgLactose 27.3 mg Corn starch 10.0 mg Low substituedhydroxypropylcellulose  3.0 mg Calcium stearate  0.8 mg Light anhydroussilicic acid  1.4 mg [Total] 75.0 mg

[0052] After 275.0 g of microcrystalline cellulose, 273.0 g of lactose,100.0 g of corn starch, 30.0 g of low substitued hydroxypropylcellulose(brand name: L-HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.), 8.0g of calcium stearate and 14.0 g of light anhydrous silicic acid (brandname: Adsolider [trademark] 101, produced by Freund Industrial Co.,Ltd.) were mixed with 50.0 g of dihydrate of calcium salt of thebenzylsuccinic acid derivative represented by the formula (I) (activecomponent), the mixture was compressed with a pressure of about 700 kgby a tabletting machine using 6 mm diameter round-faced (5R) punch toprepare tablets of the above composition.

EXAMPLE 3

[0053] Active component  22.0 mg Lactate  56.0 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Partly pregelatinized starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8 mg

[0054] After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.8 g of partly pregelatinized starch(brand name: PCS [trademark], produced by Asahi Kasei Co., Ltd.) weremixed with 2.2 g of dihydrate of calcium salt of the benzylsuccinic acidderivative represented by the formula (I) (active component), 4 g of anaqueous solution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxy-propylcellulose) was added thereto. The mixture was granulatedin a mortar, and the granules were passed through screen after drying ina shell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5R) punch to prepare tablets of the above composition.

EXAMPLE 4

[0055] Active component  22.0 mg Lactose  60.7 mg Corn starch  26.0 mgMicrocrystalline cellulose  13.2 mg Light anhydrous silicic acid  1.3 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8 mg

[0056] After 6.07 g of lactose, 2.6 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.13 g of light anhydrous silicic acid(brand name: Adsolider [trademark] 101, produced by Freund IndustrialCo., Ltd.) were mixed with 2.2 g of dihydrate of calcium salt of thebenzylsuccinic acid derivative represented by the formula (I) (activecomponent), 4 g of an aqueous solution of 6% by weight ofhydroxypropylcellulose (0.24 g as hydroxypropylcellulose) was addedthereto. The mixture was granulated in a mortar, and the granules werepassed through screen after drying in a shell dryer to yield granules of30 mesh (500 μm) or less. Calcium stearate was mixed to the granules tobe at 0.95%, and the mixture was compressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

EXAMPLE 5

[0057] Active component  22.0 mg Lactose  54.7 mg Corn starch  24.0 mgMicrocrystalline cellulose  13.2 mg Partly pregelatinized starch  8.0 mgLight anhydrous silicic acid  1.3 mg Hydroxypropylcellulose  2.4 mgCalcium stearate  1.2 mg [Total] 126.8 mg

[0058] After 5.47 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose, 0.8 g of partly pregelatinized starch (brandname: PCS [trademark], produced by Asahi Kasei Co., Ltd) and 0.13 g oflight anhydrous silicic acid (brand name: Adsolider [trademark] 101,produced by Freund Industrial Co., Ltd.) were mixed with 2.2 g ofdihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), 4 g of an aqueoussolution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxy-propylcellulose) was added thereto. The mixture was granulatedin a mortar, and the granules were passed through screen after drying ina shell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5R) punch to prepare tablets of the above composition.

EXAMPLE 6

[0059] Active component  22.0 mg Lactose  56.9 mg Corn starch  24.4 mgMicrocrystalline cellulose  14.0 mg Partly pregelatinized starch  9.0 mgHydroxypropylcellulose  2.5 mg Calcium stearate  1.2 mg [Total] 130.0 mg

[0060] After 569 g of lactose, 244 g of corn starch, 140 g ofmicrocrystalline cellulose and 90 g of partly gelatinized starch (brandname: PCS [trademark], Asahi Kasei Co., Ltd) were mixed with 2.2 g ofdihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), 416.7 g of an aqueoussolution of 6% by weight of hydroxypropylcellulose (25 g ashydroxypropyl-cellulose) was added thereto. The mixture was granulatedin a high shear mixer. The granules were dried using a fluidized-beddryer and passed through screen to yield granules of 30 mesh (50 μm) orless. Calcium stearate was mixed to the granules to be at 0.92%, and themixture was tabletted by a tabletting machine with a pressure of 500 kgusing 7 mm diameter round-faced (9.5R) punch to prepare tablets of theabove composition.

TEST EXAMPLE 1

[0061] Dissolution Test (1)

[0062] For the tablets described in Examples 1 and 2 and ReferenceExample 1, the dissolution test (a quantitative method: HPLC, adetection wave length: 220 nm) was carried out using 900 mL of firstfluid of the Japanese Pharmacopoeia at 50 rpm according to the paddlemethod, apparatus 2 of the dissolution test methods of the 13th revisedJapanese Pharmacopoeia. From the results of these dissolution tests asshown in FIG. 1, the tablets of Examples 1 and 2 showed much moreexcellent dissolution than those of Reference Example 1.

TEST EXAMPLE 2

[0063] Dissolution Test (2)

[0064] For the tablets described in Examples 3 to 6 and ReferenceExamples 2 to 9, the dissolution test (a quantitative method: UWabsorbance determination, a detection wave length: 205 nm) was carriedout using 900 mL of first fluid of the Japanese Pharmacopoeia at 50 rpmaccording to the paddle method, apparatus 2 of the dissolution testmethods of the 13th revised Japanese Pharmacopoeia. From the results ofthese dissolution tests as shown in FIG. 2, the tablets of Examples 3 to6 showed much more excellent dissolution than those of Reference Example3 to 9.

TEST EXAMPLE 3

[0065] Compatibility Test

[0066] One gram of each of the following various additives was mixedwith 1 g of dehydrate of calcium salt of the benzyl-succinic acidderivative represented by the formula (I), and the mixture was placedfor two weeks under a condition of temperature at 60° C. and relativehumidity of 80%. Then its appearance was observed.

[0067] Additives:

[0068] Partly pregelatinized starch (brand name: PCS [trademark],produced by Asahi Kasei Co., Ltd)

[0069] Carmellose (brand name: NS-300 [trademark], produced by GotokuYakuhin Co., Ltd)

[0070] Carmellose calcium (brand name: ECG-505 [trademark], produced byGotoku Yakuhin Co., Ltd)

[0071] Croscarmellose sodium (brand name: Ac-Di-Sol, produced by AsahiKasei Co., Ltd)

[0072] Light anhydrous Silicic acid (brand name: Adsolider [trademark]101, Freund Industrial Co., Ltd.)

[0073] The results are shown in the following Table 1. The dihydrate ofcalcium salt of the benzylsuccinic acid derivative represented by theformula (I) was stable in combination with partly pregelatinized starchor light anhydrous silicic acid, but caused an incompatible combinationwith carmellose, carmellose calcium or croscarmellose sodium. TABLE 1Additives Appearance Partly pregelatinized starch No change CarmelloseColored with pale yellow Carmellose calcium Colored with faint yellowCroscarmellose sodium Colored with faint yellow Light anhydrous silicicacid No change

TEST EXAMPLE 4

[0074] Stability Test

[0075] The tablets described in Example 3 and 4 and Reference Example 2were placed for 1 week under a condition of temperature at 60° C. andrelative humidity of 80%, and then appearance of the tablets, amounts oftheir decompositions and dissolution time periods using first fluid ofthe Japanese Pharmacopoeia were examined. As the results, the tabletsdescribed in Reference Example 2 containing carmellose changed a colorof appearance into faint yellow indicating an increase ofdecompositions. However, the tablets described in Examples 3 and 4 usingrespectively partly pregelatinized starch and light anhydrous silicicacid did not detect any changes, and their dissolution time periods didnot change and consequently the tablets were extremely stable.

1-3 (canceled).
 4. A method for correcting postprandial hyperglycemiccondition without causing hypoglycemic condition between meals,comprising: administering to a human patient with postprandialhyperglycemic condition an immediate release oral pharmaceuticalcomposition comprising as an active ingredient a calcium salt of abenzylsuccinic acid represented by the formula:

or its hydrate, and a disintegrating agent, wherein said disintegratingagent is silicon dioxide or partly pregelatinized starch, and wherein75% or more of said active ingredient releases within 20 minutes ofadministering said oral composition.
 5. The method of claim 4, whereinsaid disintegrating agent is silicon dioxide, and wherein said silicondioxide is present in an amount of 0.5 to 5% by weight of the totalweight of said composition.
 6. The method of claim 4, wherein saiddisintegrating agent is partly pregelatinized starch, and wherein saidpartly pregelatinized starch is present in an amount of 5 to 20% byweight of the total weight of said composition.